1-beta-aryloxyethyltetrahydro-isoquinolines



United States Patent Oflice 3,389,141 Patented June 18, 1968 3,389,141 l-p-ARYILOXYETHYLTETRAHYDRO- ISUQUINOLINES Thomas A. Montzlra, Manlius, NY, assignor to Bristol- Myers Company, New York, N.Y., a corporation of Deiaware N Drawing. Filed May 16, 1966, Ser. No. 556,151 12 Claims. (Cl. 260-286) ABSTRACT OF THE DISCLOSURE 1-fl-aryloxyethyl-2-methy1-6, 7-di1nethoxy 1,2,3,4-tetrahydroisoquinolines, wherein aryl is substituted or unsubstituted phenyl, pyrrolyl, pyridyl, thiazolyl or thienyl are useful as analgesic agents.

This invention relates to a novel series of basic chemicals and their acid addition salts which are useful analgesic agents and, more particularly, to certain substituted 1-,8-ary1oXyethyl 2-methyl-6,7 dimethoxy-l,2,3,4-tetrahydroisoquinolines.

There is provided by the present invention a member selected from the group consisting of compounds of the formula CHSO N-CH:

HzGH -O-Ar wherein Ar is a member selected from the group consisting of The preferred embodiments of the present invention are the compounds of the formula CHaO i N-CHs X wherein X and Y have the meaning set forth above and their nontoxic pharmaceutically acceptable salts and, particularly, the two compounds (and their salts) of the formula OHBO tm o-@a wherein X is hydrogen or chloro, which are exceptionally effective analgesic agents.

Included within the present invention are the acid addition salts prepared by reaction of these basic compounds with organic and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, maleic acid, tartaric acid, citric acid, sulfamic acid, glycolic acid, succinic acid, ascorbic acid and the like.

The term (iower)alkyl as used herein refers to straight and branched chain saturated monovalent aliphatic hydrocarbon radicals having from one to ten carbon atoms inclusive, 6.55. methyl, ethyl, propyl, isopropyl, butyl, normal and secondary and. tertiary butyl, amyl, decyl, etc.

The compounds of the p'resent invention are prepared as shown schematically below by reacting the appropriate ,B-aryloxypropionic acid or acid halide such as the acid chloride, with 3,4-dimethoxyphenethylamine to form the amide, cyclizing the amide, as with phosphoryl chloride, to the 1-substituted-dihydroisoquinoline, reducing the last, as with a borohydride, to the corresponding tetrahydroisoquinoline and finally methylating at the 2-position, thus:

OCH;

OOH:

An alternate procedure as exemplified below follows the scheme:

Thus the starting fi-aryloxypropionic acids or acid halides and the alternative starting ,B-aryloxypropionaldehydes may be prepared by the methods reported in the literature.

The fl-aryloxypropionic acids or acid halides are used to acylate 3,4-dimethoxyphenethylamine in the normal manner and the amide so produced is cyclized as With oxides or chlorides of phosphorus and reduced as with alkali metal metal aluminum hydride or borohydride to the tetrahydroisoquinoline or in accordance with the procedures on pages 250 and 254 of volume IV, Richter, The

Chemistry of Carbon Compounds, Elsevier Publishing- Co., Inc., New York, New York, 1947, and on pages 347-353 of volume IV, Elderfield, Heterocyclic Compounds, Wiley, New York, New York, 1952, and United States Patent No. 2,683,146 and Great Britain Patent No. 926,493.

The tetrahydroisoquinoline is then methylated in the 2- position by the usual techniques used to methylate aliphatic secondary amines, eg. with formic acid and formaldehyde. Thus, the introduction of the methyl group may be carried out according to known methods, for example, by treating the starting material, i.e., the l,6,7trisubstituted-l,2,3,4-tetrahydroisoquinoline, with a one-molar equivalent of a reactive ester of methanol. A reactive ester of methanol is particularly one formed with a strong inorganic acid, e.g. hydrochloric, hydrobromic, hydriodic, sulfuric and the like, or a strong organic sulfonic acid, e.g. methane sulfonic, ethane sulfonic, Z-hydroxyethane sulfonic, p-toluene sulfonic acid and the like; reactive esters are therefore, for example, the methyl halides, e.g. chloride, bromide, or iodide, dimethyl sulfate and methyl p-toluene sulfonate and the like. The reactive ester is preferably reacted with the starting material in the form of a metal compound, particularly of an alkali metal, e.g. lithium, sodium and the like compound; the latter is prepared by treatment with a suitable reagent capable of forming such compound, for example, with an alkali metal hydride, e.g. sodium hydride and the like, or any other equivalent reagent. The formation of the metal compound, as well as the treatment of the latter with the reactive ester is preferably carried out in the presence of a suitable inert solvent, if necessary, while cooling or at an elevated temperature and/or in a closed vessel and/ or in the atmosphere of an inert gas, e.g., nitrogen.

The methyl group may also be introduced according to other methods, for example, by treating the 1,6,7-trisubwherein Ar is as defined above (and preferably a metal salt thereof, such as the sodium or potassium salt) with a reagent of the formula C H3 0 e z i N@.. c in wherein Z represents one equivalent of an inert anion. The preferred anions include the halides (chloride, bromide and iodide), sulfate, (lower)alkyl sulfate and sulfonates, such as p-toluenesulfonate and p-bromobenzenesulfonate, but other anions are equally useful and need not even be nontoxic as the anion does not appear in the final pharmaceutical product prepared by reaction of this reagent with, for example, a compound of the formula Ar-O-Na as illustrated in Example 1 below.

These intermediate quaternary salts are prepared, in one procedure, by the treatment with a kali, e.g. Na CO of the reaction product of the alcohol of the formula CIIsO 1 onto NGH3 ornornoni With SOL 11 SQBI' (CH SO p-CH C H SO Cl,

p-BrC H SO Cl or the like. The anion Z is of little consequence in such active intermediates since the chemical reactivity resides in the cation. The anion Z is defined as an inert anion to exclude unusual anions containing additional substituents, such as phenolic hydroxyl groups, capable of further reaction with these quaternary salts. As thus prepared, Z may be chloride, bromide, methanesulfonate, ethancsulfonate, p-toluenesulfonate, p-bromobenzenesulfonate or the like. By exchange reactions of the conventional type, Z can be replaced by other anions, e.g. phosphate, fluoride, malate, succinate, fumarate, oleate, etc. The salts obtained through these variations of Z may in some cases have special advantages due to solubility, ease of crystallization, etc. but these are all subsidiary to the chemical reactivity of the compound which is independent of the character of Z In a preferred embodiment, the compounds of the present invention are prepared by the reaction of a compound of the formula Ar-OH wherein Ar is as defined above (and preferably a metal salt thereof, such as the sodium or potassium salt) with a reagent of the formula wherein X and Y are each hydrogen, chloro, bromo, fluoro, trifluoromethyl, nitro (lower) alkyl or (lower)alkoxy. This reaction is preferably conducted in an inert, organic solvent, e.g., dimethylformamide, at a temperature from 20 C. to 100 C.

The preparation of this reagent is illustrated for the case where X is hydrogen and Y is para-bromo as follows: CH3) 6 00.0111

CzHsO-C=C NH: OHaO" 00303115 CHaO- 00202115 01330 NH-OH=C comm onto q -IIo1 CH3) NH 00,151

-CzH| CIISO NH lHgCOaCgHg CHQO 01 CH3O N-orn HgCOgCgHg;

onto

-HC1 OH N- CH LHgCHgOH (III) 6,7 dimethoxy-1,2,3,4-tetrahydroisoquinoline-l-acetic acid ethyl ester oxalate (1) [A. L. Bluhm and W. J. Gensler, J. Org. Chem, 21, 336-339 (1956)].To a stirred solution of 216.9 g. (1 mole) distilled diethyl ethoxymethylencmalonate in 1 liter of absolute ethanol was added slowly 181.2 g. (1 mole) of distilled homoveratrylamine in a nitrogen atmosphere. The reaction mixture was stirred for 16 hours at room temperature and then concentrated to dryness. The resultant oil was taken up in 2 liters of 24% hydrochloric acid, heated on a steam bath for 4 hours and then concentrated to drymess to give a yellow oil. This oil was taken up in 1 liter of absolute ethanol, filtered to remove insoluble material, saturated with gaseous hydrogen chloride with cooling, stored at room temperature for one day and then concentrated to dryness to give an oil. This was retaken up in one liter of absolute ethanol, saturated with gaseous hydrogen chloride with cooling, stored at room temperature for one day and again concentrated to dryness. The resultant brown oil was basified with aqueous sodium carbonate, extracted with chloroform, dried over sodium sulfate, and concentrated to an oil which gave a crystalline oxalate with 90 g. of oxalic acid from acetone. One recrystallization from 95% ethanol yielded 228.1 g. (61.7%) of 6,7 dimethoxy 1,2,3,4-tetrahydroisoquinoline-l-acetic acid ethyl ester oxalate. Several recrystallizations from 95% ethanol gave an analytical sample M.P. 136-164 C. (poorly defined).

Analysis.-Calcd for C H NO -C H O C, 55.28; H, 6.26; N, 3.79. Found: C, 55.28; H, 6.25; N, 3.81.

6,7 dimethoxy Z-methyl-l,2,3,4-tetrahydroisoquinoline-l-acetic acid ethyl ester hydrochloride (II) [A. Brossi et al., Helv. Chim. Acta, 43, 583-593 (1960)].- To 3.8 g. (0.0135 mole) of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-l-acetic acid ethyl ester, obtained from the oxalate by neutralization with sodium carbonate, was added 1.2 ml. of 40% formaldehyde and 3.6 ml. of 88% formic acid. The reaction mixture was heated on a steam bath for 2 hours. Three ml. of 6 N hydrochloric acid were added and the solution was concentrated to dryness to yield 4.5 g. of crude crystalline 6,7-dimethoxy- 2 methyl 1,2,3,4-tetrahydroisoquinoline-l-acetic acid ethyl ester hydrochloride. One recrystallization from absolute ethanol gave analytical material, M.P. 179- 183 C.

Analysis.-Calcd for C H NO -HCl: C, 58.26; H, 7.34; N, 4.25. Found: C, 58.36; H, 7.38; N, 4.32.

6,7 dimethoxy 1 fi-hydroxyethyl-Z-methyh1,2,3,4- tetrahydroisoquinoline hydrochloride (IIll).-To a stirred suspension of 7.6 g. (0.2 mole) of lithium aluminum hydride in 100 ml. of tetrahydrofuran was added slowly 58.5 g. (0.2 mole) of 6,7dirnethoxy-2-methyl-1,2,3,4- tetrahydroisoquinoline-l-acetic acid ethyl ester (obtained from the hydrochloride by neutralization with sodium carbonate) in ml. of tetrahydrofuran. The suspen sion was refluxed for 4 hours. Twenty-five ml. of water were cautiously added and the suspension was stirred with warming until white. Anhydrous sodium sulfate was added and the solids removed by filtration. The filtrate was concentrated to dryness to give 49.9 g. (99.3%) of an oil which gave crystalline 6,7-dimethoxy-l-B-hydroxyethyl Z-methyl 1,2,3,4 -tetrahydroisoquinoline hydrochloride from acetone. One recrystallization from absolute ethanol yielded 42.6 g. of analytical material, M.P. 179-182 C.

Analysis.-Calcd for C H NO -HClz C, 58.43; H, 7.71; N, 4.87. Found: C, 58.26; H, 7.88; N, 4.77.

[2,1 a] azetidino-6,7-dirnethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolinium p-bromobenzenesulfonate (IV).- To a stirred solution at room temperature of 5.3 g. (.021 mole) of 6,7-dimethoxy-1- 8-hydroxyethyl-2-methyl-1,2,3, 4-tetrahydroisoquinoline (obtained from the hydrochloride by neutralization with sodium carbonate) in 100 ml. of chloroform was added 5.5 g. (.0216 mole) of p-bromobenzenesulfonyl chloride. Stirring was continued for 4 hours. Anhydrous sodium carbonate (11.2 g.) was added and stirring was continued for 16 hours. The mixture was filtered and the filtrate concentrated to give 9.6 g. (97%) of crude crystalline material. Several recrystallizations from isopropanol yielded analytically pure [2,1-a]azetidino 6,7 dimethoxy 2 methyl-1,2,3,4-tetrahydroiso quinolinium p-bromobenzenesulfonate, M.P. 182-184.5 C.

Analysis.-Calcd for C H BrNO S: C, 51.07; H, 5.14; N, 2.98. Found: C, 51.01; H, 5.29; N, 2.92.

As its hydrochloride salt, the preferred compound of the present invention has the structure CHaO l -H C1 N-CHa OHsO utes before the phenyl-p-quinone is injected, the reduction in induced writhing at the end of the first hour was found to be 100% and 62% respectively for this compound. This compound was also shown to be a potent analgesic by the standard rat-tail flick test.

The following examples Will serve to illustrate the present invention without limiting it thereto.

Example 1.Preparation of 1-(,8-3,4-dichlorophenoxyethyl) 6,7, dimethoxy 2 methyl 1,2,3,4 tetrahydroisoquinoline hydrochloride CHaO -HC1 N-CH;

To a stirred solution of 1.37 g. (0.0084 mole) 3,4-

dichlorophenol in ml. of dried dimethylformamide 3 water and extracted 3 times with ethyl acetate. These extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated to give an oil. This oil was taken up in acetonitrile, Washed with n-pentane to remove mineral oil, and concentrated to give 3.0 g. of a clear oil which gave a crystalline hydrochloride from acetone-dry hydrogen chloride. One recrystallization from isopropanol yielded 2.7 g. (82%) of white crystalline material, l-(fi- 3,4 dichlorophenoxyethyl) 6,7 dimethoxy 2 methyl- 1,2,3,4 tetrahydroisoquinoline hydrochloride, M.P. 171.5174.0 C.

Analysz'S.-C-a1cd for C20H23C12N03'HC11 C, H, 5.59; N, 3.28. Found: C, 55.76; H, 5.73; N, 3.33.

By similar procedures, the compounds of the following Examples 2 through 11 were prepared in the indicated amounts and with the properties stated.

Example 2.-Preparation of 1-(B-4-chlorophenoxyethyl)- 6,7 dimethoxy 2 methyl 1,2,3,4 tetrahydroisoquinoline hydrochloride 0.38 g. (0.0092 mole) sodium hydride 1.05 g. (0.0084 mole) p-chlorophenol 3.6 g. (0.0076 mole) [2,l-a]azetidino-6,7-dimethoxy-2- methyl 1,2,3,4 tetrahydroisoquinolinium p bromobenzenesulfonate yielded 1.8 g. l (fi 4-chlorophenoxyethyl)-6,7- dimethoxy 2 methyl 1,2,3,4 tetrahydroisoquinoline hydrochloride from absolute ethanol, M.P. 190-194 C.

Analysis.--Calcd for C I-I ClNO -HC1: C, 60.30; H, 6.33; N, 3.52. Found: C, 60.03; H, 6.42; N, 3.44.

Example 3.Preparation of 6,7-dirnethoxy-2-methyl-l- (B phenoxy ethyl) 1,2,3,4 tetrahydroisoquinoline hydrochloride Cir .6 g. (0.0076 mole) [2,l-a].azetidino-6,7-dimethoxy-2- methyl l,2,3,4 tertahydroisoquinolinium p bromobenzenesulfonate yielded 1.4 g. (52%) 6,7-dimethoxy-2-methyl-1-([3- phenoxyethyl) l,2,3,4-tetrahydroisoquinoiine hydrochloride from isopropanol, M.P. 181-184" C.

Analysis.-Calcd for Cg H25NO 'HC1: C, 66.01; H, 7.20; N, 3.85. Found: C, 66.01; H, 7.29; N, 3.83.

Example 4.Preparation of 6,7 iimethoxy 1 (fl-p-methoxyphenoxyethyl) 2 methyl 1,2,3,4 tetrahydroisoquinoline hydrochloride 0.38 g. (0.0092 mole) sodium hydride 1.04 g. (0.0084 mole) 4-methoxyphenol 3.6 g. (0.0076 mole) [2,1-a]azetidino-6,7-dimethoxy-2- methyl l,2,3,4 tetrahydroisoquinolinium p bromobenzenesulfonate yielded 2.1 g. (70%) 6,7-dimethoxy l (fl-p-methoxyphenoxyethyl) 2 methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride from absolute ethanol M.P. 178-181.5 C.

AnaZysis.-Calcd for C H NO -HCl: C, 64.03; H, 7.16; N, 3.56. Found: C, 64.27; H, 7.29; N, 3.63.

Example 5.Preparation of 6,7-dimethoxy-2-methyl-l- (,B p-trifiuoromethylphenoxyethyl)-l,2,3,4-tetrahydroisoquinoline hydrochloride 0.38 g. (0.0092 mole) sodium hydride 1.35 g. (0.0084 mole) p-triiluoromethylphenol 3.6 g. (0.0076 mole) [2,1-a]azetidin0-6,7 dimethoxy-Z- methyl l,2,3,4-tetrahydroisoquinolinium p bromobenzenesulfonate yielded 2.4 g. (73.5%) of 6,7-dimethoxy-2-methyl-1-(5- p triiluoromethylphenoxyethyl) 1,2,3,4 tetrahydroisoquinoline hydrochloride from ethanol, M.P. 199- 206 C.

Analysis.-Calcd for C H RNO 'HCI: C, 53.53; H, 5.61; N, 3.25. Found: C, 58.25; H, 5.90; N, 3.29.

Example 6.Preparation of 1-(fi-2,6-dichlorophenoxyethyl) 6,7 dimethoxy 2 methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride CIIaO- I T ncl 01130 43113 or I on on -o- 0.38 g. (0.0092 mole) sodium hydride 1.37 g. (0.0084 mole) 2,6-dichlorophenol 3.6 g. (0.0076 mole) [2,l-a]azetidino-6,7-dimethoxy-2- methyl 1,2,3,4 tetrahydroisoquinolinium p bromobenzenesulfonate yielded 2.7 g. (82.4%) of 1-(B-2,6-dichlorophenoxyethyl) 6,7 dimethoxy Z-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride from 95% ethanol, M.P. 188 C.

9 Analysis.--Calcd for C20H23Cl N03HClZ C, 55.50; H, 5.59; N, 3.24. Found: C, 55.48; H, 5.66; N, 3.07.

Example 7.--Preparation of 1 3 m chlorophenoxyethyl) 6,7 dimethoxy-Z-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride 0.38 g. (0.0092 mole) sodium hydride 1.07 g. (0.0084 mole) m-chlorophenol 3.6 g. (0.0076 mole) [2,1-a]azetidino-6,7-dimethoxy-2- methyl 1,2,3,4 tetrahydroisoquinolinium p bromobenzesulfonate 0.38 g. (0.0092 mole) sodium hydride 0.94 g. (0.0084 mole) p-fluorophenol 3.6 g. (0.0076 mole) [2-1-a]azetidino-6,7-dimethoxy-2- methyl 1,2,3,4 tetrahydroisoquinolinium p bromobenzenesulfonate yielded 1.8 g. (62%) of 6,7-dimethoxy-1-(B-p-fiuorophenoxyethyl) 2 methyl 1,2,3,4 tetrahydroisoquinoline hydrochloride hemiethanate from 95% ethanol, M.P. 177.5-1875" C.

Analysis.--Calcd fOI' C H FNO -HCl- /zC H OH: C, 62.29; H, 6.97; N, 3.46. Found: C, 62.53; H, 7.09; N, 3.49.

Example 9.Preparation of 1-(fl-o-chlorophenoxyethyl)- 6,7 dimethoxy 2 methyl 1,2,3,4 tetrahydroisoquinoline hydrochloride (0.0092 mole) sodium hydride (0.0084 mole) o-chlorophenol g. (0.0076 mole) [2,1-a]azetidino-6,7-dimethoxy 2- methyl 1,2,3,4 tetrahydroisoquinolinium p hromobenzenesulfionate Example 10.Preparation of 1 (,6 p bromophenoxy- 10 ethyl) 6,7 dimethoxy 2 methyl 1,2,3,4 tetrahydroisoquinoline hydrochloride -H 01 N-CHa 0.38 g. (0.0092 mole) sodium hydride 1.45 g. (0.0084 mole) p-bromophenol 3.6 g. (0.0076 mole) [2,1-a]azetidino-6,7-dimethoxy-2- methyl 1,2,3,4 tetrahydroisoquinolinium p bromobenzenesulfonate yielded 2.0 g. (59%) of 1-(fi-p-bromophenoxyethyl)-6,7- dimethoxy 2 methyl 1,2,3,4 tetrahydroisoquinoline hydrochloride from ethanol, M.P. 179-189 C.

Analysis.-Calcd for C H BrNO -HCl: C, 54.25; H, 5.69; N, 3.16. Found: C, 54.23; H, 5.78;; N, 3.08.

Example 11.-Preparation of 1-(B-ZA-dichlorophenoxyethyl) 6,7 dimethoxy 2 methyl 1,2,3,4 tetrahydroisoquinoline hydrochloride hernihydrate or-rso- ClElIrCHz-O- Cl 0.38 g. (0.0092 mole) sodium hydride 1.37 g. (0.0084 mole) 2,4-dichlorophenol 3.6 g. (0.0076 mole) [2,1-a]azetidino-6,7-dimethoxy-2- methyl 1,2,3,4 tetrahydroisoquinolinium p bromohenzenesulfonate yielded 2.0 g. (61%) of 1-(,B-2,4-dichlorophenoxyethyl)- 6,7 dimethoxy 2 methyl 1,2,3,4 tetrahydroisoquinoline hydrochloride hemihydrate from 95 ethanol, M.P. 146-149" C.

Analysis.Cald for C2gI'I23Cl2NO3'HCl' /2H2O: C, 54.25; H, 5.69; N, 3.16; H 0, 2.04. Found: C, 54.35; H, 5.62; N, 3.04; H O, 2.41.

Example 12.-Preparation of 6,7-dimethoxy-2-methyl- 1(,6 p nitrophenoxyethyl) 1,2,3,4 tetrahydroisoquinoline hydrochloride A solution of 1.35 g. (0.0084 mole) of sodium p-nitrophenoxide in 2 5 ml. dimethylformamide was treated with 3.6 g. (0.0076 mole) of [2,1-a]azetidino-6,7-dimethoxy- 2 methyl 1,2,3,4 tetrahydroisoquinolinium p bromobenzenesulfonate and stirred at room temperature for 4 days. The solution was concentrated to dryness under vacuum. The residue was dissolved in water and extracted three times with ethyl acetate. These extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated to give an oil which gave a crystalline hydrochloride from absolute ethanol. One recrystallization from 95% ethanol gave 1.8 g. (58%) of analytical material, M.P. 179-189 C.

Analysis.-Calcd for C H N 0 -HCl: C, 58.74; H, 6.16; N, 6.85. Found: C, 58.72; H, 6.30; N, 6.61.

1 1 Example 13 When, in the procedure of Example 1, 3,4-dichlorophenol is replaced by an equal molar amount of Z-triiiuoromethylphenol, Z-fluorophenol,

2-bromophenol,

4-methylphenol, 4-isopropylphenol, Z-methoxyphenol,

3 ,4-dirnethoxyphenol, Z-hydroxypyridine, 4-hydroxypyridine, 2-hydroxythiazole, 2-hydroxythiophene, 3-hydroxythiophene, 2-chloro-3-hydroxythiophene, 3-chloro-2-hydroxythiophene, 4-chloro-2-hydroxythiazole,

5 -trifluorom ethyl-Z-hydroxythiazole, 5-'chloro-2-hydroxythiazole, 3-hydroxypyrrole, Z-hydroxypyrrole, 3-chloro4-hydroxypyrrole, 2,6-dichloro-4-hydroxypiperidine, 4,5 -dichloro-2-hydroxythiazole, 2,3-dich]ore-4-hydroxythiophene, and 2,3 -dichloro-4-hydro :ypyrrole,

there are obtained,

1- {3-2-trifiuoromethylphenoxyethyl) -6,7-dimethoxy- 2-n1ethyl-1,2,3,4-tetrahydroisoquinoline hydrochloride,

1- /3-2-fluorophenoxyethyl) -6,7-dimeth0Xy-2-methyll,2,3,4-tetrahydroisoquinoline hydrochloride,

1- [B-Z-bromophenoxyethyl) -6,7-dirnethoxy-2-methyl- 1,2,3,4-tetrahydroisoquinoline hydrochloride,

1- B-4-methylphenoxyethyl) -6,7-dimethoXy-2-methyl- 1,2,3,4-tetrahydroisoquinoline hydrochloride,

1- ,8-4-isopropylphenoxyethyl -6,7-dimethoxy-2-methyl- 1,2,3,4-tetrahydroisoquinoline hydrochloride,

1- ,B-Z-methoxyphenoxyethyl) -6,7-dimethoxy-2-methyl- 1,2,3,4-tetrahydroisoquinoline hydrochloride,

l{(3-3,4-dimethoxyphenoxyethyl)-6,7-dirnethoXy-2- methyl-l ,2,3,4-tetrahydroisoquinoline hydrochloride,

1- fi-Z-pyridyloxyethyl) -6,7-dirnethoxy-2methyl- 1,2,3,4-tetrahydroisoquinoline hydrochloride,

1- [3-4-pyridyloxyethyl -6,7-dimethoxy-2-methyll,2,3,4-tetrahydroisoquinoline hydrochloride,

1- (B-Z-thiazolyloxyethyl -6,7-dimethoXy-2-rnethyl- 1,2,3,4-tetrahydroisoquinoline hydrochloride,

1- Q-Z-thienyloxyethyl -6,7-dimethoXy-2-rnethyl- 1,2,3,4-tetrahydroisoquinoline hydrochloride,

1- (3-3-thienyloxyethyl -6,7-din1ethoxy-2-methyl- 1,2,3,4-tetrahydroisoquinoline hydrochloride,

1- B-2-chloro-3 -thienyloxyethyl -6,7-dimethoxy-2- methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride,

1- (5-3 -chloro-Z-thienyloxyethyl -6,7-dimethoXy-2- methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride,

1- 3-4-chloro-2-thiazolyloxyethyl) -6,7-dimethoxy-2- methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride,

1- B-5-trifluoromethyl-Z-thiazolyloxyethyl) -6,7-

dimethoXy-2-methyl-l,2,3,4-tetrahydroisoquinoline hydrochloride,

1- (Q-S-chloro-2-thiazolyloxyethyl -6,7-dimethoxy-2- methyl-l,2,3,4-tetrahydroisoquinoline hydrochloride,

1- ,8-3 -pyrrolyloxyethyl -6,7-dirnethoXy-2-methyl- 1,2,3,4-tetrahydroisoquinoline hydrochloride,

1- B-Z-pyrrolyloxyethyl -6,7-din1ethoxy-2-methyl- 1,2,3,4-tetrahydroisoquinoline hydrochloride,

1- 6-3-chloro-4-pyrrolyloxyethyl -6,7-dimethoXy-2- methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride,

1- [3-2,6-dichloro-4-pyridyloxyethyl) -6,7-dimethoXy-2- methyl-1,2,3 ,4-tetrahydroisoquinoline hydrochloride,

1- [3-4,5-dichloro-2-thiazolyloxyethyl -6,7-dirnethoXy-2- methyl-l,2,3,4-tetrahydroisoquinoline hydrochloride,

1- (5-23 -dichloro-4-thienyloxyethyl -6,7-dimethoxy-2- methyl-l,2,3,4-tetrahydroisoquinoline hydrochloride and 1- 6-2,3-dichloro-4-pyrrolyloxyethyl) -6,7-dimethoxy- Z-methyl-l,2,3,4-tetrahydroisoquinoline hydrochloride,

respectively.

The compounds of the present invention contain an asymmetric carbon atom, and thus normally occur as a racemic mixture of the two optical isomers. Both isomers and mixtures thereof are included Within the scope of the present invention. The individual isomers are prepared in pure form by first resolving the intermediate of the formula 01130 Nflcna iSO'lIOl isolrzer CHZCHZOH with an optically active acid, e.g., dextro-rotatory substituted tartranilic acids having the formula 0 O IIo-g oH-CI-I ii-NII- Q -R CIJII 11 l I wherein R is hydrogen, chloro, bromo or nitro and R is hydrogen, chloro or brorno, but R and R are not each hydrogen and preferably those having the formulae and then reacting the resolved intermediates according to the method previously described herein.

The dextro-rotatory substituted tartranilic acids resolving agents are prepared by the consecutive steps of:

(a) Heating a mixture of (|)-2,3-diacetyl-succinic anhydride or its functional equivalent as an acylating agent for primary amines and an aniline, and preferably a substituted aniline having the formula 13 tartranilic acid, said substituent comprising preferably at least one nitro, chloro or bromo group,

(b) Separating said enantiomeric salts by fractional crystallization and then (c) Converting said separated enantiomeric salts to the respective optical isomers of the organic amine, preferably by treatment with a strong base.

The +)-2,3-diacetylsuccinic anhydride used as a starting material is prepared according to Organic Syntheses, Collected Volume IV, page 242, Wiley (1963) or preferably as "exemplified below. It is apparent that it can be replaced by the corresponding mono-acid halides or mono-mixed anhydrides and other functional equivalents for the acylation of anilines.

The following examples are given to illustrate the preparation of the resolving agents and the preparation of the optical isomers of the compounds of this invention. All temperatures are given in degrees centigrade.

PREPARATION OF RESOLVING AGENTS Example 1 layers were separated and the methylene chloride layer U was extracted with 100 ml. more water. The combined aqueous layers were heated on a steam bath, treated with Example 3 (+)-2,3-diacetoxysuccinic anhydride-A mixture of tartaric acid (150 g., 1 mole) in 700 ml. acetic anhydride was warmed with stirring until the exothermic reaction started. Heating was discontinued and the reaction was allowed to run its course (about 2-3 hours). The colorless solution was concentrated to dryness at reduced pressure. Final drying under high vacuum gave a quantitative yield of (+)-2,3-diacetoxysuccinic anhydride (216 g.) of good purity. This material may be recrystallized from ethyl acetate-Skellysolve B it better purity is desired. Recrystallized material has a melting point of 133.0133.5 and [111 +605 (c.==6.2 acetone).

Substituted tartranic acids V (ac).-(+) 2,3 diacetoxysuccinic anhydride (21.6 g., 0.1 mole) and substituted aniline (0.11 mole) in 200 ml. of methylene chloride were heated under reflux for 3 hours. This solution was treated with a solution of potassium hydroxide (21 g. of 86% potassium hydroxide pellets; 0.32 mole) in 200 ml. water and stirred vigorously for 15 minutes. The methylene chloride layer was separated and extracted with 100 ml. water. The combined aqueous layers were stirred for 2 hours, then warmed to solution, treated with decolorizing carbon (if necessary), filtered through diatomaceous earth (Celite), acidified with 35 m1. concentrated hydrochloric acid and cooled immediately for crystallization. The crystals were collected, washed with water, and then recrystallized from the indicated solvent.

H OH Y X,Y Cryst. solvent Meme) 1 V(a-o), Yield,

M.P., O. percent Va 2-NO 2 H2O (HCD +89.8 (0.8, H2O) 196.0-198. 5O Vb 2,4-di Cl. H2O or 1101 10 +100.7 (1.6)- 182. 5-192. 5 59 V0.-. Z-Cl H2O +99.4 (1 0) 1805-1825 47 Vd-.. 4-Cl Ethanol-H2O--. +l08.9 (1.6 1933. 0-195. 0 85 V6 4-Br (hydrate) Ethanol-H2O +905 (1.8) 198.5-L5 67 1 Unless otherwise indicated rotations were taken in 95% ethanol. 2 This material sometimes crystallizes containing potassium salt. Recrystallization from dilute HCl converts to 100% acid.

a This material tends to form a gel on recrystallization. It is recommended that it not be recrystallized.

decolorizing carbon, filtered hot through diatomaceous earth (Celite), acidified with 50 ml. concentrated hydrochloric acid and cooled at 5 overnight. The crystals were collected and washed with 100 ml. cold water to yield 32 g. yellow crystals. This material was taken up in 300 ml. hot water, treated with 15 m1. concentrated hydrochloric acid and cooled. Collection of the crystals gave 28 g. (52%) of 2'-nitrotartranilic acid. A sample. was recrystallized from n-propanol for analysis, M.P. 196.0-198.0, [ml +71.3 (c.=2.5, ethanol), [(11 +89.8 (c.=0.83, H O).

Analysis.Calcd for c H N O z C, 44.45; H, 3.73; N, 10.37. Found: C, 44.41; H, 3.79; N, 10.31.

Example 2 2,4 diehlorotartranilic acid.(+)-2,3-diacetylsuccinic anhydride (22 g., 0.1 mole) and 2,4-dich1oroaniline (18 g., 0.11 mole) in 150 ml. methylene chloride were stirred together for two hours. A solution of 21 g. potassium hydroxide (87% pellets; 0.32 mole) in 200 ml. water was added and the two-phase system stirred vigorously for one hour. The methylene chloride layer was separated, extracted with 100 ml. water and discarded. The combined aqueous extracts were warmed on a steam bath, filtered, acidified with ml. concentrated hydrochloric acid and cooled for crystallization. Collection of this material gave 17 g. (59%) colorless (+)-2,4-dichlorotartranilie acid. Several crystallizations Example 4 2 chlorotartranilic acid.(+)-2,3 diacetoxysuccinic anhydride (21.6 g., 0.1 mole) and 2-chloroaniline (12.8 g., 0.1 mole) in 100 ml. of methylene chloride were heated under reflux for one hour. This solution was treated with a solution of potassium hydroxide (22 g., 86% pellets; 0.32 mole) and the methylene chloride was removed under reduced pressure. The remaining aqueous solution was heated on a steam bath 20 minutes, filtered hot, acidified with 35 ml. concentrated hydrochloric acid and cooled to yield 12.1 g. (47%) crystalline (+)-2'-chlorotartranilic acid. Recrystallization from water gave analytical material, M.P. l80.5-182.5, [@1 {-99.4 (e.=1.65, ethanol).

Analysis.--Calcd for C H ClNO C, 46.26; H, 3.88; N, 5.40. Found: C, 46.22; H, 3.48; N, 5.32.

Example 5 (+)-4'-chlorotartranilic acid.(+) 2,3 diacetoxysuccinic anhydride (22 g., 0.1 mole) and 4-chloroaniline (15 g., 0.12 mole) in 150 ml. methylene chloride were stirred together for one hour. This solution was treated with a solution of potassium hydroxide (21 g., 86% pellets, 0.32 mole) in 50 ml. water. This two-phase system was stirred vigorously for one hour. The layers were separated and the organic layer extracted with ml. water. The combined aqueous layers were heated to drive off any residual methylene chloride, filtered and acidified with 30 ml. concentrate hydrochloric acid. After cooling, the crystals were collected to give 24.2 g. (90%) (+)-4- chlorotartranilic acid. Recrystallization twice from 3:1 waterzethanol gave an analytical sample, M.P. 193.0- 195.0, [M +108.9 (c.=1.64, 95% ethanol).

Analysis.-Calcd for C H ClNO C, 46.26; H, 3.88; N, 5.40. Found: C, 46.65, 46.62; H, 4.04, 4.05; N, 5.34.

Example 6 (+)-4'-bromotartranilic acid hydrate.-(+)-2,3 diacetoxysuccinic anhydride (21.6 g., 0.1 mole) and 4- bromoaniline (17.2 g., 0.1 mole) were placed with 200 ml. methylene chloride and heated under reflux for 3 hours. This solution was treated with a solution of potassium hydroxide (21 g., 86% pellets, 0.32 mole) in 200 ml. Water and stirred vigorously for ten minutes. The methylene chloride layer was separated and extracted with 100 ml. water. The combined aqueous layers were stirred for two hours, warmed, filtered and acidified to give 20.5 g. (67%) crystalline (+)-4'-bromotartranilic acid hydrate. This was recrystallized from ethanol-water with a decolorizing carbon treatment to give g. analytically pure (+)-4'-bromotartranilic acid hydrate, M.P. 198.5-201.5, +905 (c.=1.8, 95% ethanol).

Analysis.-Calcd for C H BrNO -H Oz C, 37.28; H, 3.76; N, 4.35; H O, 5.59. Found: C, 37.07; H, 3.61; N, 4.32; H O, 5.68.

Example 7.-Resolution of (i) 6,7 dimethoxy 1 B- hydroxyethyl-2-methyl-1,2,3,4-tetrahydroisoquinoline CHaO I CHBO N-CIIs isomer (1; isomer HQCHZOH To a warm solution of 73.1 g. (0.292 mole) of (i)- 6,7-dimethoxy-l-fi-hydroxyethyl 2 methyl-1,2,3,4-tetrahydroisoquinoline in 375 ml. of 95 ethanol was added a warm solution of 39.4 g. (0.146 mole) of (+)-2'-nitrotartranilic acid in 375 ml. of 95 ethanol. The crystals (75.9 g.) were collected after storage at 5 C. for hours. One recrystallization from 750 ml. of 80% ethanol gave 69.8 g. (92%) of material, M.P. 193.5-195.5.

This material was converted to its free base by neutralization with aqueous sodium carbonate and extraction with ethyl acetate. Concentration of the ethyl acetate extracts gave 30.0 g. of oil. This oil gave a crystalline hydrochloride from isopropanol and 10 ml. of concentrated hydrochloric acid. One recrystallization from 150 ml. of absolute ethanol gave 22.3 g. (55%) of (+)-6,7- dimethoxy-l-fi-hydroxyethyl 2 methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride, M.P. 177-180" +22.7 (c.=2.05, chloroform).

Analysis.-Calcd for C H NO -HCl: C, 58.43; H, 7.71; N, 4.87. Found: C, 58.67; H, 7.81; N, 4.63.

The mother liquor from the original crystallization was concentrated to /5 its original volume, and treated with 1.0 g. (+)-2-nitrotartrani1ic acid in 25 ml. of 95% ethanol. The solution was concentrated to dryness and the resultant oil taken up in ethyl acetate, filtered, washed wtih aqueous sodium carbonate, dried over anhydrous sodium sulfate, and concentrated to dryness to give 33.6 g. of an oil. This oil gave a crystalline hydrochloride from acetone-dry hydrogen chloride. One recrystallization from 95% ethanol gave 24.4 g. (60%) of (-)-6,7- dimethoxy-l-,6-hydroxyethyl 2 methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride, M.P. 177-l79, [111 22.8 (c.=2.02, chloroform).

Analysis.-Calcd for C H NO -HCl: C, 58.43; H, 7.71; N, 4.87. Found: C, 58.41; H, 7.81; N, 4.67.

Example 8 ()-[2,1 a]azetidino 6,7 dimethoxy 2 methyl- 1,2,3,4 tetrahydroisoquinolinium p bromobenzenesulfonate.(+) 6,7 dimethoxy 2 methyl 1,2,3,4- tetrahydroisoquinoline hydrochloride (23.8 g., 0.083 mole) was converted to its free base by neutralization with sodium carbonate and extraction with 200 ml. chloroform. The chloroform extract was dried over sodium sulfate and filtered. This solution was then treated with 23.2 g. (0.091 mole) of p-brornobenzene sulfonyl chloride and stirred for four hours at room temperature. Anhydrous sodium carbonate (44 g.) was then added and stirring was continued sixteen hours. The reaction mixture was filtered and the filtrate concentrated to give 38 g. of crude crystalline material. One recrystallization from isopropanol gave 26.8 g. (69%) of analytical material, M.P. 178180, [M 115.7 (c.=2.02, chloroform).

Analysis.-Calcd for C H BrNO S: C, 51.07; H, 5.14; N, 2.98. Found: C, 51.24; H, 5.24; N, 2.85.

Example 9 -[2,1-a] azetidino-6,7-dimethoxy-Z-methyl-1,2,33,4- tetrahydroisoquinolinium p bromobenzenesulfonate.- ()-6,7 dimethoxy 2 methyl 1,2,3,4-tetrahydroisoquinoline hydrochloride (22.6 g., 0.079 mole) was converted to its free base by neutralization with sodium carbonate and extraction with 200 ml. chloroform. The chloroform extract was dried over sodium sulfate and filtered. This solution was then treated with 21.8 g. (0.085 mole) of p-bromobenzenesulfonyl chloride and stirred for four hours at room temperature. Anhydrous sodium carbonate (41.5 g.) was added and stirring was continued for sixteen hours. The reaction mixture was filtered and the filtrate concentrated to give 39 g. of crude crystalline material. One recrystallization from isopropanol gave 26.0 g. (70.3%) of analytical material, M.P. 179.5-180.5, [a] -]1l4.2 (c.=2.00 chloroform).

Analysis.Calcd for C H BrNO S: C, 51.07; H, 5.14; N, 2.98. Found: C, 51.11; H, 5.12; N, 2.75.

Example 10 (S)-1-(/3-3,4-dichlorophenoxyethyl)-6,7 dimethoxy-Z- methyl 1,2,3,4 tetrahydroisoquinoline hydrochloride- To a stirred solution of 1.37 g. (0.0084 mole) 3,4-dichlorophenol in 25 ml. of dried dimethylformamide maintained in a nitrogen atmosphere was added 0.38 g. (0.0092 mole) of a 58.6% dispersion of sodium hydride in mineral oil. After stirring for 15 minutes, 3.6 g. (0.0076 mole) of()- [2,1-a]azetidino-6,7 dimethoxy 2 methyl-1,2,3,4,- tetrahydroisoquinolinium p-bromobenzenesulfonate was added. Stirring at room temperature was continued for twenty hours. This solution was concentrated to dryness under vacuum. The residue was dissolved in water and extracted three times with ethyl acetate. These extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated to give an oil. This oil was taken up in acetonitrile, washed with n-peutane to remove mineral oil, and concentrated to give 3.0 g. of a clear oil which gave a crystalline hydrochloride from acetone-dry hydrogen chloride. One recrystallization from isopropanol yielded the product, (S)-1-(,B-3,4-dichlorophenoxyethyl)-6,7-dimethoxy-2-rnethyl-1,2,3,4 tetrahydroisoquinoline hydrochloride.

This is the (S) isomer in the nomenclature of Oahu, Ingold and Prelog, Expcrientia, X11 (3), 81-94 (Mar. 15, 1956).

Example 11 (R) 1 ([+3,4-dichlorophenoxyethyl)-6,7-dimethoxy- 2 methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride.- To a stirred solution of 1.37 g. (0.0084 mole) 3,4-dichlorophenol in 25 ml. of dried dimethylformamide maintained in a nitrogen atmosphere was added 0.38 g. (0.0092 mole) of a 58.6% dispersion of sodium hydride in mineral oil. After stirring for 15 minutes, 3.6 g. (0.0076 mole) of (+)-[2,1-a1azetidino 6,7 dimethoxy-Z-methyl-l,2,3,4- tetrahydroisoquinolinium p-bromobenzenesulfonate was added. Stirring at room temperature was continued for twenty hours. This solution was concentrated todryness under vacuum. The residue was dissolved in water and extracted three times with ethyl acetate. These extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated to give an oil. This oil was taken up in acetonitrile, washed with n-pentane to remove mineral oil, and concentrated to give 3.0 g. of a clear oil which gave a crystalline hydrochloride from acetone-dry hydrogen chloride. One recrystallization *from isopropanol yielded the product, (R) 1 (/3-3,4-dichlorophenoxyethyl)-6,7-dimethoxy 2 methyl-I,2,3,4-tetrahydroisoquinoline hydrochloride.

This is the (R)isomer. All or'virtually all of the analgesic activity resides in this (R)-- isomer, whether it is in the form of the free base or an acid addition salt.

The compounds of this invention may be administered as the free bases or in the form of their nontoxic addition salts. They may be compounded and formulated into pharmaceutical preparations in unit dosage form for oral or parenteral administration with organic or inorganic solid materials or liquids which are pharmaceutically acceptable carriers. The compositions may take the form of tablets, powders, granules, capsules, suspensions, solu tions and the like. Such compositions are considered within the scope of this invention.

The compounds of this invention when administered orally or parenterally in an effective amount are effective in the treatment of pain.

While this invention has been described and exemplified in terms of its preferred embodiment, those skilled in the art will appreciate that modifications can be made without departing from the spirit and scope of the invention.

I claim:

1. A member selected from the group consisting of compounds of the formula CHSO NCH3 wherein Ar is a member selected from the group consisting of CHBO I N-CHa X wherein X and Y are each a member selected from the group consisting of hydrogen, chloro, bromo, fluoro, trifiuoromethyl, methyl, ethyl, methoxy and ethoxy and non- 18 toxic pharmaceutic'ally acceptable acid addition salts thereof.

3. A compound of claim 1 having the formula OHZO N-CHE G1 and nontoxic pharmaceutically acceptable acid addition salts thereof. 7

4. A compound of claim 1 having the formula i N- C H; B r

and nontoxic pharmaceutically acceptable acid addition salts thereof.

5. A compound of claim 1 having the formula orno t i or-no or;

and nontoxic pharmaceutically acceptable acid addition salts thereof.

6. A compound of claim 1 having the formula l N-CH3 NOI and nontoxic pharmaceutically acceptable acid addition salts thereof.

7. A compound of claim 1 having the formula CHaO onto- I N"CH3 F and nontoxic pharmaceutically acceptable acid addition salts thereof.

8. A compound of claim 1 having the formula and nontoxic pharmaceutically acceptable acid addition salts thereof.

9. A compound of claim 1 having the formula orno or-no- CH@ crnonro and nontoxic pharmaceutically acceptable acid addition salts thereof.

10. The compound of claim 1 having the formula and nontoxic pharmaceutically acceptable acid addition salts thereof.

01130 I l I v v 12. The (R) isomer of the compound of claim 11.

01x30 N-cm 7 5 V I References Cited xzonro gw UNITED STATES PATENTS a 2,785,166 3/1957 Cusic 260288 and nontoxlc pharmaceutlcally acceptable and add1t1on 3,042,671 Lombardine et a1.

salts thereof. 10

11.111 dfl' 1h" thf 1 avmg e NICHOLAS s. RIZZO,"Primary Examiner.

OHQO I 1 D. G. DAUS, Assistant Examiner. 

